Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N⁶-methyladenosine (m⁶A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m⁶A and altered 3′-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.

RNA 的转录后修饰构成了一个新兴的基因表达调控层。去甲基化酶脂肪量和肥胖相关蛋白 (FTO)，一种N ⁶ -甲基腺苷 (m ⁶A), 已被证明在癌症中发挥作用，但其对肿瘤进展的贡献和潜在机制仍不清楚。在这里，我们报告了与侵袭、转移增加和临床结果更差相关的上皮癌中广泛的 FTO 下调。在体外和体内，FTO 沉默促进癌症生长、细胞运动和侵袭。在人源性肿瘤异种移植物 (PDX) 中，FTO 药理学抑制有利于肿瘤发生。从机制上讲，我们证明 FTO 耗尽通过增加 m ^{6引发上皮-间充质转化 (EMT) 程序}A 和改变了沿 Wnt 信号级联的关键 mRNA 的 3'-末端加工。因此，FTO 敲低通过 EMT 起作用，使小鼠异种移植物对 Wnt 抑制敏感。因此，我们将 FTO 确定为跨上皮癌、Wnt 触发的 EMT 和肿瘤进展的关键调节剂，并揭示了 FTO 低肿瘤的治疗可利用的脆弱性。